NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity

The RAS→RAF→MEK→ERK pathway is hyperactivated in the majority of human lung adenocarcinoma (LUAD). However, the initial activating mutations induce homeostatic feedback mechanisms that limit ERK activity. How ERK activation reaches the tumor-promoting levels that overcome the feedback and drive mali...

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Bibliographic Details
Published in:	Oncogene Vol. 41; no. 2; pp. 293 - 300
Main Authors:	Ingram, Kelley, Samson, Shiela C., Zewdu, Rediet, Zitnay, Rebecca G., Snyder, Eric L., Mendoza, Michelle C.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 05-01-2022 Nature Publishing Group
Subjects:	101/1 13/106 14/19 14/5 42/109 42/41 631/67/1612/1350 631/80/86 64/60 82/51 96/63 Adenocarcinoma Animal models Animals Apoptosis Brief Communication Cell Biology Cell growth Disease Models, Animal Disease Progression Dual Specificity Phosphatase 6 - metabolism Extracellular signal-regulated kinase Extracellular Signal-Regulated MAP Kinases - metabolism Feedback Human Genetics Humans Internal Medicine Kinases Lung cancer Lung Neoplasms - genetics MAP Kinase Signaling System - genetics Medicine Medicine & Public Health Metabolic pathways Metastases Metastasis Mice Mutation Oncology Phosphatase Proteins Raf protein Thyroid Nuclear Factor 1 - metabolism Thyroid transcription factor 1 Transcription factors Tumor cells Tumors Xenografts
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Summary:	The RAS→RAF→MEK→ERK pathway is hyperactivated in the majority of human lung adenocarcinoma (LUAD). However, the initial activating mutations induce homeostatic feedback mechanisms that limit ERK activity. How ERK activation reaches the tumor-promoting levels that overcome the feedback and drive malignant progression is unclear. We show here that the lung lineage transcription factor NKX2-1 suppresses ERK activity. In human tissue samples and cell lines, xenografts, and genetic mouse models, NKX2-1 induces the ERK phosphatase DUSP6, which inactivates ERK. In tumor cells from late-stage LUAD with silenced NKX2-1 , re-introduction of NKX2-1 induces DUSP6 and inhibits tumor growth and metastasis. We show that DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo and that DUSP6 expression is sufficient to inhibit RAS-driven LUAD. Our results indicate that NKX2-1 silencing, and thereby DUSP6 downregulation, is a mechanism by which early LUAD can unleash ERK hyperactivation for tumor progression.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 co-first author ELS and MCM conceptualized the study. KI, SCS, RGZ, RZ, ELS, and MCM carried out the investigation and extraction of the results. SCS, ELS, and MCM designed the methods and carried out formal analysis and interpretation of the results. MCM managed data curation, project administration, acquisition of study funding, and writing the original manuscript draft. All co-authors were involved in review and editing of the manuscript. Contributions
ISSN:	0950-9232 1476-5594
DOI:	10.1038/s41388-021-02076-x